Development of fetal hemoglobin inducers targeting epigenetic and oxidative stress mechanisms
针对表观遗传和氧化应激机制的胎儿血红蛋白诱导剂的开发
基本信息
- 批准号:10385817
- 负责人:
- 金额:$ 36.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-20 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:Abnormal HemoglobinsAddressAdherenceAdolescentAdultAfrica South of the SaharaAminolevulinateAnemiaAnimal ModelAnnexinsAntioxidantsApoptosisBACH1 geneBindingBiological AvailabilityBiological ModelsBone MarrowButyric AcidsCD34 geneCellsChromatin StructureClinicalClinical ResearchClinical TrialsCompetitive BindingCountryDataDecitabineDeoxyribonuclease IDevelopmentDiseaseDoseDrug CombinationsDrug KineticsEmbryoEpigenetic ProcessErythroid CellsErythropoiesisExperimental ModelsFDA approvedFetal DevelopmentFetal HemoglobinFrightFumaratesFutureGene ActivationGene Expression RegulationGenesGeneticGenetic TranscriptionGoalsHalf-LifeHematological DiseaseHematopoiesisHemeHemoglobinHemoglobinopathiesHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHumanHypersensitivityIndividualInfantInheritedInvestigational DrugsKnockout MiceKnowledgeLegal patentLocus Control RegionMediatingMolecularMusNamesOralOutcomeOxidative StressPainPapioPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacologic SubstancePharmacotherapyPhase I Clinical TrialsPhenotypePlasmaPopulationProdrugsProteinsResponse ElementsRestRoleScheduleSeveritiesSickle Cell AnemiaSiteSourceStainsStem cell transplantTFRC geneTestingToxic effectTransgenic MiceTransgenic OrganismsUnited StatesWorkbasebeta Globinchemotherapyclinically relevantcostdrug developmentdrug efficacyeffective therapyerythroid differentiationfetalgamma Globingene therapyhistone modificationhydroxyureaimprovedin vivoinhibitorintravenous administrationmouse modelnovelpre-clinicalprogenitorpromotersickle erythroidsicklingsmall moleculestem cellstranslational impacttranslational studytransplantation therapy
项目摘要
PROJECT SUMMARY
The β-hemoglobinopathies are the most common genetic blood disorders worldwide, but limited effective
treatments have been developed over the last three decades. Induction of normal, but developmentally silenced
fetal hemoglobin (HbF) expression reduces anemia and ameliorates clinical severity of sickle cell disease (SCD).
Histone deacetylases (HDACs) have been shown to promote silencing of the fetal γ-globin genes in adult
erythroid cells, and HDAC inhibitors were shown to increase HbF in patients with β-hemoglobinopathies. But
these had limitations for pharmaceutical application due to the need for intravenous administration and their anti-
proliferative effects. This project focuses on creating safe and effective small-molecule oral HbF-inducing agents.
In one study, we observed HbF induction with a novel oral conjugate of butyric acid (BA) and δ-aminolevulinate
(ALA), named AN-233, and a BACH1 inhibitor that enhanced NRF2 expression in sickle erythroid progenitors
and β-YAC mice. Next, focusing on these small-molecule agents, we will test the central hypothesis that
modulation of γ-globin gene transcription through epigenetic histone modifications and enhanced NRF2 binding
mediate HbF induction. Specific Aim 1. will test the prediction that the oral prodrug AN-233 induces HbF
expression through epigenetic histone modifications and NRF2 activation, using relevant preclinical
animal models. Treatments conducted in β-YAC and SCD transgenic mice will establish the optimal oral dose
and schedule of AN233 that induces HbF without producing anti-proliferative effects. The phenotypic effects of
AN-233 in SCD mice related to oxidative stress, and its anti-sickling ability will be tested. To achieve an indicator
of human drug efficacy we will test AN-233 in anemic juvenile baboon to determine HbF induction and effects
on hematopoiesis. We will define mechanisms of γ-globin activation by AN-233 involving epigenetic histone
acetylation and the role of ALA in heme synthesis and NRF2 activation. Specific Aim 2. Test the prediction
that the oral BACH1 inhibitor HPP-D enhances NRF2 binding to the γ-globin promoter ARE to activate
transcription. We will establish the BACH1 inhibitor HPP-D, as an HbF inducer using sickle erythroid progenitors
and conduct combination drug treatments with clinically relevant agents including hydroxyurea and decitabine.
Subsequently, molecular mechanisms of HbF induction by HPP-D through enhanced NRF2 binding in the γ-
globin promoter will be evaluated. Finally, the ability of HPP-D to induce HbF expression in the preclinical SCD
mice will establish in vivo efficacy. Expected outcomes include establishing specific potent HDAC inhibitors and
agents that modulate β-globin locus chromatin structure in favor of γ‐globin transcription, for subsequent clinical
studies to address the unmet need for improved disease-modifying therapy for SCD.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Betty Sue Pace其他文献
Betty Sue Pace的其他文献
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{{ truncateString('Betty Sue Pace', 18)}}的其他基金
Development of fetal hemoglobin inducers targeting epigenetic and oxidative stress mechanisms
针对表观遗传和氧化应激机制的胎儿血红蛋白诱导剂的开发
- 批准号:
10602522 - 财政年份:2020
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE: Functional and Translational Genomics of Blood Disorders
PRIDE:血液疾病的功能和转化基因组学
- 批准号:
8822523 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE-Functional and Applied Genomics of Blood Disorders
PRIDE-血液疾病的功能和应用基因组学
- 批准号:
8145262 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE-Functional and Translational Genomics of Blood Disorders
PRIDE-血液疾病的功能和转化基因组学
- 批准号:
10557179 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE: Functional and Translational Genomics of Blood Disorders
PRIDE:血液疾病的功能和转化基因组学
- 批准号:
9292356 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE-Functional and Applied Genomics of Blood Disorders
PRIDE-血液疾病的功能和应用基因组学
- 批准号:
8521359 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE-Functional and Applied Genomics of Blood Disorders
PRIDE-血液疾病的功能和应用基因组学
- 批准号:
8219409 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE-Functional and Applied Genomics of Blood Disorders
PRIDE-血液疾病的功能和应用基因组学
- 批准号:
8311817 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
PRIDE-Functional and Translational Genomics of Blood Disorders
PRIDE-血液疾病的功能和转化基因组学
- 批准号:
10343750 - 财政年份:2010
- 资助金额:
$ 36.2万 - 项目类别:
Genome-wide Association Study: Fetal Hemoglobin Phenotypes in Sickle Cell Disease
全基因组关联研究:镰状细胞病中的胎儿血红蛋白表型
- 批准号:
7785754 - 财政年份:2009
- 资助金额:
$ 36.2万 - 项目类别:
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